Fragment evolution for GPCRs: the role of secondary binding sites in optimization

We developed a docking-based fragment evolution approach that extends orthosteric fragments towards a less conserved secondary binding pocket of GPCRs. Evaluating 13 000 extensions for the beta(1)- and beta(2)-adrenergic receptors we synthesized and tested 112 bitopic molecules. Our results confirmed the positive contribution of the secondary binding pocket to both potency and selectivity optimizations.

Automated summary

A new docking-based fragment evolution approach was developed to extend orthosteric fragments towards a less conserved secondary binding pocket of GPCRs. Evaluation of 13,000 extensions for beta(1)- and beta(2)-adrenergic receptors resulted in the synthesis and testing of 112 bitopic molecules, confirming the positive contribution of the secondary binding pocket to potency and selectivity optimizations.